Synthesis and biological activity of pseudopeptides inhibitors of Ras farnesyl transferase containing unconventional amino acids

• Published in: Farmaco (Società chimica italiana : 1989) 1999-11, Vol.54 (11), p.785-790
• Main Authors: Caliendo, Giuseppe, Fiorino, Ferdinando, Grieco, Paolo, Perissutti, Elisa, De Luca, Stefania, Giuliano, Ada, Santelli, Giovanni, Califano, Daniela, Severino, Beatrice, Santagada, Vincenzo
• Format: Article
• Language: English
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Amino Acids - analysis; Animals; Antineoplastic agents; Biological and medical sciences; Brain - enzymology; Cattle; Cell Line; Cell Line, Transformed; Cell Survival - drug effects; Cellular in vitro activity; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; Medical sciences; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Pharmacology. Drug treatments; Phenol derivative; Ras farnesyltransferase inhibitor; Rats
• ISSN: 0014-827X; 1879-0569
• DOI: 10.1016/S0014-827X(99)00104-4

A study was performed on the structure–activity relationships of a series of phenol derivatives, CVFM analogs, derived from the two most active compounds of a first series ( 1 A and 1 B ) of inhibitors of Ras farnesyl transferase (FTase) that we have recently described. We report the synthesis and the activity of a second series of compounds in which the phenylalanine residue was replaced by unconventional aromatic and non-aromatic amino acids, with varying electronic, lipophilic, steric and conformational properties. The compounds showed to be significantly less active than reference compounds against FT, with the only exception of derivative 3 A (IC 50=3 μM), which is slightly more active than 1 A but not 1 B . Subsequently we tested the effects of compounds 1 A , 1 B and 3 A , 3 B on the anchorage-dependent growth of two epithelial cell lines of rats, FRTL-5 and the same line v-Ha-ras transformed. Compound 3 A derived from lead compound 1 A , showed an appreciable selectivity against transformed cells. In contrast, compounds derived from derivative 1 B had only a modest cellular activity.